Abstract
After internalization of triglyceride-rich lipoproteins (TRL) in hepatoma cells, TRL particles are immediately disintegrated in the early endosomal compartment. This involves the targeting of lipids and apoprotein B along the degradative pathway and the recycling of TRL-derived apoE through recycling endosomes. Re-secretion of apoE is accompanied by the concomitant association of apoE and cellular cholesterol with high-density lipoproteins (HDL). Since epidemiological data showed that apoE3 and apoE4 have differential effects on HDL metabolism, we investigated whether the intracellular processing of TRL-derived apoE4 differs from apoE3-TRL. In this study, we demonstrated by radioactive and immunofluorescence uptake experiments that cell-surface binding and internalization of TRL-derived apoE4 are increased compared with apoE3 in hepatoma cells. Pulse-chase experiments revealed that HDL-induced recycling, but not disintegration and degradation, of apoE4-enriched TRL is strongly reduced in these cells. Furthermore, impaired HDL-induced apoE4 recycling is associated with reduced cholesterol efflux. Studies performed in Tangier fibroblasts showed that apoE recycling does not depend on ATP-binding cassette transporter A1 activity. These studies provide initial evidence that impaired recycling of apoE4 could interfere with intracellular cholesterol transport and contribute to the pathophysiological lipoprotein profile observed in apoE4 homozygotes.
Highlights
Intestinal chylomicrons and liver-derived very low-density lipoproteins (VLDL)1 represent triglyceride-rich lipoproteins (TRL) that deliver lipids and lipophilic vitamins to other cells of the body
Since epidemiological data showed that apoE3 and apoE4 have differential effects on high-density lipoprotein (HDL) metabolism, we investigated whether the intracellular processing of TRL-derived apoE4 differs from apoE3TRL
Some observations have indicated that the internalization and intracellular processing of TRL-derived apoprotein E (apoE) isoforms may help to explain the differences of apoE isoforms in lipid metabolism
Summary
Intestinal chylomicrons and liver-derived very low-density lipoproteins (VLDL) represent triglyceride-rich lipoproteins (TRL) that deliver lipids and lipophilic vitamins to other cells of the body. We recently discovered that HDL stimulates and serves as an acceptor for recycled apoE in hepatocytes in vitro and in vivo [10, 13] This new link between TRL-derived apoE and HDL metabolism is associated with cholesterol efflux and involves the internalization of HDL particles to preexisting endosomes containing TRL-derived apoE [13]. We demonstrated that HDL-induced recycling, but not internalization, degradation, or disintegration of TRL-derived apoE4, is impaired compared with apoE3. This process does not depend on the ATP-binding cassette transporter A1 (ABCA1) activity. Impaired apoE4 recycling could explain the low apoE protein and cholesterol content of HDL, which is associated with the human apoE4 allele (20, 26, 30 –32)
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